Abstract
Antipsychotic medication is effective in the treatment of psychotic symptoms. However, between 20% and 40% of schizophrenic patients exhibit inadequate or poor response [1]. This appears to be the case not only with the use of ‘typical’ antipsychotic medications, but also with the use of the newer ‘atypical’ medications. Considering that the problem of treatment-resistant schizophrenia is an important and difficult one, several approaches have been made by clinicians in order to deal with the clinical challenge. Combined application of atypical antipsychotic drugs is an often used and established strategy [2]. An overview of results suggests that combinations with clozapine and a second atypical antipsychotic were mostly beneficial in the described patients with reduction of positive and negative symptoms [3], [4]. Aripiprazole is a novel atypical antipsychotic drug chemically characterized as a quinolinone derivative [5]. It is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and has antagonist activity at the 5-HT2A receptor. It has a low-to-moderate affinity for the 5-HT2C receptor and H1 receptor. In placebo-controlled studies, aripiprazole was shown to be effective in improving both the positive and negative symptoms in patients with schizophrenia or schizoaffective disorder. Furthermore, aripiprazole treatment was associated with a good safety and tolerability profile, with minimal liability for the side effects that limit treatment with other agents, including extrapyramidal side effects, elevated prolactin, weight gain, sedation and QTC prolongation [5]. Here, we report our first experience with the combination of clozapine and aripiprazole in two patients with treatment-resistant schizophrenia. The purpose of combination treatment was to reduce positive symptoms and side effects.
In two male-inpatients with paranoid schizophrenia (36 years and 44 years, meeting ICD-10-criteria), we found a suboptimal response to high-dose clozapine treatment (675 mg and 850 mg daily dosage) with persistent positive and negative symptoms. They complained about side effects (sedation, hypersalivation, weight gain) that led to compliance problems. Several monotherapies with typical and atypical antipsychotics have proven to be ineffective in both patients. Electrocardiogram, electroencephalogram and computed tomography of the brain revealed no abnormal findings, whereas the blood tests showed increased liver enzymes. A dose reduction of clozapine was not tolerated regarding the positive symptoms. Fifteen milligrams of aripiprazolwas added daily in both the cases. Productive positive symptoms decreased within 6 weeks and clozapine could be reduced. After 16 weeks, the daily clozapine dosewas reduced to 425 mg and 600 mg without recurrence of the positive symptoms. As a result of the reduced dose of clozapine, the side effects subsided in both the cases with the focus on daytime fatique and hypersalivation, which in turn led to better compliance. In one patient, we found a slight weight loss of 2.6 kg.
The cases indicate that the combination of clozapine and aripiprazole represents a new therapeutic strategy in cases of treatment-resistant schizophrenia, which is a frequent clinical problem. The regimen follows a neurobiological rationale with a highly synergistic antipsychotic potency without increasing the risk of adverse effects. Improvement of psychopathological state and side effects could be achieved, and drug doses were lower than with monotherapy. Additional prospective studies are needed in order to systematically evaluate this new treatment strategy.